Non-insulin dependent diabetes mellitus (NIDDM) is a common problem in the elderly population of the USA and in the rest of the world. The aims of this project are: to find regulatory signals controlling insulin secretion from beta cells of the pancreas; to study the mechanism of action of gastrointestinal hormones called incretins (e.g. glucagon-like peptides (GLP) and glucose insulinotropic peptide (GIP]) on stimulation of insulin secretion after short term exposure; and to study the mechanism of action of incretins on beta cells proliferation after long-term exposure. Incretins have many desirable effects in addition to stimulation of insulin secretion. They inhibit glucagon secretion from pancreatic alpha cells and enhance insulin action at insulin target tissues. The cloned rat GLP receptor has been transfected into different cell lines to study further the signal transduction involved in GLP action. Furthermore, the screening of peptides with structural similarity to GLP will allow the understanding of structure-function relationship and the development of new therapeutic agents for NIDDM.